Investigations in this laboratory continue to focus on mechanisms of immune regulation of connective tissue metabolism. Lymphocytes and monocytes activated in vitro produce unique mediators which stimulate proliferation of fibroblasts. Furthermore, lymphocytes and monocytes isolated from inflamed synovial tissue or fluid of rheumatoid arthritis patients spontaneiously release these factors emphasizing their potential role in the fibroplasia and fibrosis associated with chronic inflammatory lesions. Depletion of lymphocytes in patients with severe refractory rhuematoid arthritis by leukapheresis results in clinical improvement in some patients. This clinical responsiveness is associated with an enhancement of immune function and appears to be the result of depletion of a functionally abnormal subset of mononuclear cells. Furthermore, in an experimental rat model, the onset of streptococcal cell wall induced arthritis is the consequence of a deficient immune system in the genetically susceptible strains of rats. Thus, lymphocytes and monocytes appear to be responsible for the initiation and perpetuation of synovial inflammation in arthritis, and their products may provide the molecular link between the inflammatory response and the subsequent changes in connective tissue which accompany inflammation.